Water-based cannabinoid and opioid compositions

ABSTRACT

Embodiments of the invention relate to methods for the manufacture of a protein-bound cannabinoid, comprising: obtaining a cannabinoid or cannabis in a form selected from the group consisting of cannabis smoke, cannabis vapor, cannabinoid solution and cannabis extract, and combining the cannabis smoke, vapor, cannabinoid solution or cannabis extract with an aqueous solution or suspension comprising a plasma protein to form a protein-bound cannabinoid. Further embodiments relate to aqueous solutions comprising a plasma protein-bound cannabinoid and pharmaceutical compositions comprising cannabinoids bound to plasma protein.

RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 16/876,143,filed on May 18, 2020, which is a continuation of U.S. patentapplication Ser. No. 14/661,573, filed on Mar. 18, 2015, which claimsthe benefit under 35 U.S.C. 119(e) of U.S. Provisional Application61/954,634, filed on Mar. 18, 2014 and U.S. Provisional Application62/096,558, filed on Dec. 24, 2014. The contents of the forgoingapplications are hereby incorporated by reference in their entirety.

TECHNICAL FIELD

Embodiments of the invention relate to compositions comprisingcannabinoids.

BACKGROUND

Cannabis is a genus of plants comprising the species Cannabis sativa, C.indica, and C. ruderalis. Cannabis plants have been cultivated for avariety of uses including making fibers (hemp), medicinal use andrecreational drug use. Cannabis is also commonly known as marijuana.

One of the most common ways that cannabis is used for medicinal use inmany countries (also known as medical marijuana) is through smoking.Smoking cannabis is typically performed by using a pipe, by using awater-pipe (also known as a bong) which filters the smoke through waterbefore inhalation or by rolling in paper to form marijuana cigarettes,also known colloquially as “joints.” The part of the plant typicallyused for smoking is the whole flower and budding leaf.

Cannabinoids are compounds active on cannabinoid receptors in humans.Cannabinoids of plant origin, also known as phyto-cannabinoids, areabundant in plants of the Cannabis genus. Two known cannabinoids whichare present in relatively high concentrations in Cannabis sativa aretetrahydracannabinol-acid (THCA) or its decarboxylated producttetrahydracannabinol (THC) and cannabidiolic acid (CBDA) or itsdecarboxylated product cannabidiol (CBD). Psychoactive and other medicaleffects of many of the cannabinoids have been studied. For example, THCwas found to have psychoactive (calming) effects, analgesic effects,antioxidant effects and to increase appetite. CBD was found to haveneuroprotective effects and to have ameliorative effects in patientswith schizophrenia and Parkinson's disease. Additional cannabinoids,active cannabis compounds and their effects are disclosed in ElSohly etal., incorporated herein by reference.

In addition to cannabinoids, terpenoids and flavonoids are present incannabis species. Some terpenoids were found to have biological effectand to contribute to a portion of the pharmacological effects ofcannabis plant matter. Exemplary terpenoids present in cannabis plantmatter include Beta-myrcene and alpha-pinene. Terpenoids and theiridentification is further described in Casano et al., incorporatedherein by reference.

Although individual chemical components of cannabis have been isolated,many jurisdictions approve the use and sale of medical cannabis plantmatter for a variety of indications. Research has shown that there arepotential benefits to medical cannabis including but not limited to:pain relief, such as chronic pain or cancer related pain, neuropathicpain; lack of appetite, and nausea such as in patients with HIV/AIDS andin patients receiving chemotherapy; autoimmune disease, such as multiplesclerosis; epilepsy; glaucoma; neurodegenerative disease andpost-traumatic stress disorder (PTSD). (Greydanus, 2013) Inflammatorydisease, such as Crohn's disease is another indication in which cannabismay have a positive effect. (Naftali, 2011)

Smoking medical cannabis, although proven to be beneficial in certainindications, has disadvantages. Since cannabis is a plant, amounts ofactive ingredients in the part of the plant being smoked may differdepending on the part of the plant and from plant to plant. Changinggrowing conditions (such as amount of light that a plant receives perday, or temperature) may vary at a cannabis growing facility therebyproviding product in which concentration of active ingredients vary overthe course of the year. As a result, a patient treated using medicalcannabis may lack control over proper dosing of active cannabinoids.

Another disadvantage of smoking medical cannabis is the negative impactof some of the constituents of cannabis smoke. The smoke from the plantmatter may comprise carcinogens in addition to the desired cannabinoids.(Melamede, 2005) In addition, heavy cannabis use through smoking hasbeen associated with accelerated pulmonary decline. (Pletcher, 2012)

Opium is a naturally occurring latex which is obtained from resin of theflower bud of the opium poppy plant known as Papaver sombiferum. Opiumand other plant matter from the opium poppy comprise manypharmaceutically active compounds known as opioids, including, forexample, morphine and codeine. Opium is a drug used in ancient as wellas modern times, as morphine is effective in a variety of indicationsand is effective in providing analgesia, treating various types of painand alleviating shortness of breath in patients. Opium may beadministered via smoking or vaporization by heating the opium and bysubsequent inhalation of the smoke or vapor.

Opium administration by smoking and/or vaporization of opium poppy plantmatter, may be disadvantageous in side effects of smoking as well aslack of control over dosing, as addressed with respect to cannabis.

SUMMARY

Embodiments of the invention provide compositions comprising cannabinoidcomponents of cannabis plant or of smoke derived from cannabis plant.Such compositions may mimic interactions between plasma proteins andsmoke/vapor comprising cannabinoids. Such compositions may obviate theneed for a patient to smoke cannabis and thereby experience thedetrimental effects associated with cannabis smoke inhalation. Methodsfor making such compositions are also provided herein. The novelcompositions may be water soluble, allowing for preparation of qualitycontrolled, accurately dosed pharmaceutical compositions foradministration and rapid absorption by humans. The compositions may becharacterized and quantified so that a patient can receive a measuredquantity of an active cannabinoid or a combination of a plurality ofcannabinoids, or other active compounds in the cannabis plant. Thecompositions may provide pharmacological benefits similar to thoseassociated with cannabis smoke, but without the detrimental effectsassociated with cannabis smoke inhalation.

An aspect of an embodiment of the invention provides a method for themanufacture of a protein-bound cannabinoid, the method comprising:heating cannabis plant matter to form a smoke and/or a vapor, andintroducing the smoke and/or vapor to an aqueous solution or suspensioncomprising a protein. Further embodiments relate to methods forisolation of an active cannabinoid from cannabis comprising: heatingcannabis plant matter to form a smoke and/or a vapor, and introducingthe smoke and/or vapor to an aqueous solution comprising a protein.

Further embodiments of the invention relate to novel compositionsderived from cannabis extract or heated cannabis extract or cannabissmoke/vapor dissolved in solvent. Cannabis extract may comprise multiplecannabinoids derived from the plant matter from which it is derived. Thecannabis extract may be combined with aqueous protein to bindcannabinoids present in the extract to aqueous proteins.

Compositions, according to embodiments of the invention may comprise acannabinoid or at least two cannabinoids bound to protein in an aqueousmedium, and optionally a pharmaceutically acceptable carrier.

Cannabinoids generally have very low solubility in water. This qualityhas previously caused difficulty in forming aqueous pharmaceuticalcompositions or extracts based on cannabis. It has been found thatbecause of low solubility of cannabinoids in water, introducing cannabisextract or smoke/vapor into an aqueous medium alone, does notsignificantly allow for the dissolution of cannabinoids in the aqueousmedium. On the other hand, when a plasma protein such as albumin isintroduced into the aqueous medium before the introduction of thecannabis extract or smoke/vapor, active cannabinoids are bound by theprotein and can dissolve in the aqueous solution.

According to an embodiment of the invention, aqueous solution comprisingcannabinoids bound to proteins may be purified and/or quantified todetermine the identity and quantity of individual cannabinoids in it.Separation of cannabinoids from each other may then also be performed.

Plasma proteins have regions with an affinity to hydrophobic moleculessuch as drugs, hormones or hydrophobic amino acids. Without being boundby theory, it is suggested that when cannabis smoke/vapor is introducedto an aqueous solution comprising a plasma protein, the plasma proteinmay bind to the cannabinoids in the smoke/vapor. It is further suggestedthat when cannabis extract is introduced to an aqueous solutioncomprising a plasma protein, the plasma protein may bind to thecannabinoids in the extract. The aqueous solution that results may thenbe purified to remove non-bound chemical components that originated inthe cannabis extract or smoke/vapor and that had dissolved in theaqueous solution. The cannabinoids that are bound by proteins, and inparticular plasma proteins such as albumin, lipoprotein, glycoprotein,and α, β, and γ globulins, may be introduced into the body of a patientin need thereof. The plasma protein-bound cannabinoid may then circulatewithin the plasma and interact with specialized plasma proteinsreceptors or release the cannabinoid within the body, providing adesired pharmacological effect. The plasma protein-bound cannabinoid mayhave a different pharmacological effect substantially equivalent to orgreater than the cannabis smoke/vapor from which it originated, withoutthe deleterious effects associated with inhalation of cannabis smoke.

According to an embodiment of the invention, a plasma protein mayincorporate a complete plasma protein or a peptide comprising a portionof a plasma protein. The portion of the plasma protein may comprise aportion which adsorbs a cannabinoid. According to an embodiment of theinvention, a plasma protein is a variant of a naturally occurring plasmaprotein.

An embodiment of the invention relates to a targeting plasmaprotein-bound cannabinoid which comprises a targeting moiety linked tothe plasma protein. The targeting moiety may be a molecule that binds toa ligand having prevalence in a certain organ or cell type in a patient.For example, the ligand may be a ligand prevalent in a cancer and lessprevalent in non-cancer cells. An advantage of such an embodiment is theability to target a plasma protein-bound cannabinoid to a specific organor type of cell or to prevent the cannabinoids from entering the centralnervous system.

Without being bound by theory, it is suggested that when a patientsmokes cannabis plant matter, the cannabinoids in the smoke/vapor whichis introduced into his/her lungs are absorbed into the patient's bloodstream and carried or bound by plasma proteins. Compositions accordingto embodiments of the invention may be beneficial in that activecannabinoids are bound by plasma proteins and easily absorbed in thebloodstream of the patient.

An aspect of an embodiment of the invention provides a method for themanufacture of a protein-bound opioid, the method comprising: heatingopium plant matter to form a smoke and/or a vapor, and introducing thesmoke and/or vapor to an aqueous solution or suspension comprising aprotein. Such methods yield novel compositions with enhanced qualitiessuch as enhanced bioavailability.

Further embodiments of the invention relate to novel compositionsderived from cannabis, comprising terpenoids and/or flavonoids.

Further embodiments of the invention relate to novel compositionsderived from opium plant matter. Opium plant matter may comprise variousopioids. The plant matter, or extract made from the plant matter may becombined with aqueous protein to bind opioids to aqueous proteins.

Compositions, according to embodiments of the invention may comprise anopioid or at least two different opioids, bound to protein in an aqueousmedium, and optionally a pharmaceutically acceptable carrier.

Naturally occurring opioids may have low solubility in water. Thisquality has previously caused difficulty in forming aqueouspharmaceutical compositions or extracts based on opium. It is suggestedthat because of low solubility of opium in water, introducing opiumsmoke/vapor into an aqueous medium alone, does not significantly allowfor the dissolution of opioids in the aqueous medium. On the other hand,when a plasma protein such as albumin is introduced into the aqueousmedium before the introduction of the opium extract or opiumsmoke/vapor, active opioids may be bound by the protein and may dissolvein the aqueous solution.

Naturally occurring pharmaceutically active ingredients from otherplants or animals may be bound to proteins using methods describedherein using similar methods to those presented herein with respect tocannabis. Non-limiting examples of such naturally occurringpharmaceutically active ingredients include: steroids, such asecdysteroids and phytoecdysteroids.

In the discussion unless otherwise stated, adjectives such as“substantially” and “about” modifying a condition or relationshipcharacteristic of a feature or features of an embodiment of theinvention, are understood to mean that the condition or characteristicis defined to within tolerances that are acceptable for operation of theembodiment for an application for which it is intended. Unless otherwiseindicated, the word “or” in the specification and claims is consideredto be the inclusive “or” rather than the exclusive or, and indicates atleast one of, or any combination of items it conjoins.

This summary is provided to introduce a selection of concepts in asimplified form that are further described below in the detaileddescription. This summary is not intended to identify key features oressential features of the claimed subject matter, nor is it intended tobe used to limit the scope of the claimed subject matter.

BRIEF DESCRIPTION OF FIGURES

Non-limiting examples of embodiments of the invention are describedbelow with reference to figures attached hereto that are listedfollowing this paragraph. Identical structures, elements or parts thatappear in more than one figure are generally labeled with a same numeralin all the figures in which they appear.

FIGS. 1A and 1B show flow diagrams depicting processes according toembodiments of the invention;

FIG. 2A depicts a chromatogram from a high performance liquidchromatography (HPLC) testing of a sample of protein-bound cannabinoidssynthesized by exposing cannabis smoke to a plasma protein solutionaccording to an embodiment of the invention;

FIG. 2B depicts a chromatogram from an HPLC testing of a sample ofcontrol solution without proteins which was exposed to cannabis smoke;

FIG. 3A depicts a graph showing inhibition of nuclear factor-kappaB(NFκB), an indicator of inflammation, at two concentrations for twocannabinoid compositions obtained by known methods, versus cannabinoidcompositions obtained according to embodiments of the invention;

FIG. 3B depicts a graph showing inhibition of nuclear factor-kappaB(NFκB), using cannabinoid compositions obtained according to embodimentsof the invention;

FIG. 4 depicts a graph showing amounts of THC adsorbed to albumin insolutions comprising varying concentrations of THC at two differenttimes of incubation; and

FIG. 5 depicts a graph shown effect of varying concentration of ethanolin aqueous solution and impact on THC adsorption to protein in resultingsolutions.

DETAILED DESCRIPTION

In the following detailed description, new methods for manufacture ofenhanced compositions comprising cannabinoids will be described indetail. Reference is now made to FIG. 1A, which shows a flow-diagramdepicting a method 100 for the manufacture of compositions comprisingcannabinoids and/or for treatment of a patient in need thereof, inaccordance with embodiments of the invention.

Method 100 comprises a block 10, which comprises producing cannabissmoke and/or vapor by heating cannabis plant material. According to anembodiment of the invention, cannabis plant material may be selectedfrom one or more than one of: leaves, flowers, trichomes, resin,tincture, extract, oil and cannabis tissue culture parts like callus.According to an embodiment, cannabis plant material comprises acombination of leaves and flowers.

According to an embodiment of the invention, cannabis plant material maycomprise a material from a cannabis species selected from the groupconsisting of: Cannabis sativa, C. indica, and C. ruderalis. In anembodiment, the cannabis species is a mixed species based on at leastone of the aforementioned cannabis species. In a preferred embodiment,the cannabis plant material comprises C. sativa.

According to an embodiment of the invention, smoke is produced bycombustion or burning of cannabis plant material. In an embodiment,smoke/vapor is produced by heating the plant material to a temperatureof between about 40° C. and to about the combustion temperature of theplant material. Combustion and/or heating of the cannabis plant mattermay be performed in a chamber suitable for collection of vapor and/orsmoke formed upon the combustion and/or heating.

Method 100 may further comprise a block 20, which comprises contactingcannabis smoke/vapor with an aqueous protein solution.

According to an embodiment of the invention, the protein is a plasmaprotein. According to an embodiment of the invention, the plasma proteinis one of or a combination of more than one of albumin, lipoprotein,glycoprotein, and α, β, and γ globulin or diluted blood plasma.According to an embodiment of the invention, the plasma protein may benaturally occurring protein or recombinant protein. According to anembodiment of the invention, the albumin may comprise human serumalbumin or bovine serum albumin or egg albumin (OVA).

Contacting the cannabis smoke/vapor with an aqueous protein solution maybe performed by collecting the smoke/vapor and bubbling it through theaqueous protein solution. Optionally, a forced-air vaporizer may be usedto contact cannabis smoke/vapor with an aqueous protein solution.Optionally, a system may be used in which smoke/vapor is streamed in tothe albumin solution stream using the Venturi effect having pipes forconducting the fluids, the pipes having varying diameters.

According to an embodiment of the invention, the aqueous solutioncomprises at least one salt and at least one buffer. According to anembodiment of the invention, the solution is substantially isotonic withblood. According to an embodiment, the solution comprises Hartmann'ssolution.

According to an embodiment of the invention the aqueous solutioncomprises between about 0.001% and about 80% plasma protein on aweight/volume (w/v) basis. According to an embodiment of the inventionthe aqueous solution comprises between about 0.01% and about 40% plasmaprotein on a w/v basis According to an embodiment, the aqueous solutioncomprises about 20% (w/v) plasma protein. According to an embodiment ofthe invention, the concentration of protein is about 10 mg/ml.

According to an embodiment of the invention, the aqueous solution maycomprise an additional non-water solvent. According to an embodiment ofthe invention, the non-water solvent is an alcohol. According to anembodiment of the invention, the alcohol may comprise ethanol. Accordingto an embodiment of the invention, the aqueous solution may comprise anon-water solvent in a concentration of about 25%-33%.

Upon contacting a cannabis smoke with an aqueous protein solution, theprotein in the aqueous solution may bind cannabinoids present in thesmoke, forming protein-bound cannabinoid. The otherwise water-insolublecannabinoid may then be dissolved in the aqueous protein solution.

Method 100 may further comprise a block 30, which comprises analyzingthe aqueous protein solution. Analysis may be performed on a sample ofthe aqueous solution or the purified wash protein to determine thecannabinoid profile (identity and quantity) of the cannabis plantmaterial. Analysis may be performed through chromatography, such as gaschromatography or HPLC.

Method 100 may further comprise a block 40, which comprises isolatingand/or purifying protein-bound cannabinoid. According to an embodimentof the invention, isolating and or purifying protein-bound cannabinoidmay comprise removing non-protein-bound dissolved compounds from thesolution. This may be performed by precipitating the protein-boundcannabinoid out of solution, for example, by adding a solvent or a saltto the solution or by denaturing the protein, for example, by heating.The precipitate may then be washed to remove non-protein bound dissolvedcomponents. According to an embodiment of the invention, purificationmay be performed through a pore-size gradient or using a dialysis tube.

Alternatively or additionally, purification of protein-bound cannabinoidmay be performed by removal of water from the solution, according toembodiments of the invention. Removal of the water may be performed byvacuum, heating, lyophilization, or a combination of any of thesemethods.

Method 100 may further comprise a block 50, which comprises combining aprotein-bound cannabinoid with an excipient to form a pharmaceuticalcomposition.

The protein-bound cannabinoid according to an embodiment of theinvention may comprise one or more than one of the following: Δ9-THC,Δ8-THC, tetrahydrocannabinoic acid (THCA), CBD, cannabidiolic acid(CBDA), cannabinol (CBN), cannabigerol (CBG), tetrahydrocannabivarin(THCV), cannabigerolic acid CBGA and cannabichromene (CBC).

The pharmaceutical compositions according to an embodiment of theinvention are conveniently presented in unit dosage form and areprepared by any of the methods well known in the art of pharmacy. In anembodiment of the invention, the unit dosage form is in the form of atablet, capsule, lozenge, wafer, patch, ampoule, vial, metered-doseinhaler or pre-filled syringe.

The compositions of the present invention are generally administered inthe form of a pharmaceutical composition comprising at least one activecomponent together with a pharmaceutically acceptable carrier ordiluent.

For oral administration a pharmaceutical composition can take the formof solutions, suspensions, tablets, pills, capsules, powders, and thelike. Tablets containing various excipients such as sodium citrate,calcium carbonate and calcium phosphate are employed along with variousdisintegrants such as starch and preferably potato or tapioca starch andcertain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tableting purposes. Solid compositions ofa similar type are also employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the components of this invention can be combined withvarious sweetening agents, flavoring agents, coloring agents,emulsifying agents and/or suspending agents, as well as such diluents aswater, ethanol, propylene glycol, glycerin and various like combinationsthereof.

The compositions according to embodiments of this invention may also beadministered in a controlled release formulation such as a slow releaseor a fast release formulation. Such controlled release dosagecomposition may be prepared using methods well known to those skilled inthe art.

For purposes of parenteral administration, solutions in sesame or peanutoil or in aqueous propylene glycol can be employed, as well as sterileaqueous solutions of the corresponding water-soluble salts. Such aqueoussolutions may be suitably buffered, if necessary, and the liquid diluentfirst rendered isotonic with sufficient saline or glucose. These aqueoussolutions are especially suitable for intravenous, intramuscular,subcutaneous and intraperitoneal injection purposes.

Pharmaceutical compositions according to embodiments of the inventionmay contain an active amount of 0.1%-95% of the protein-boundcannabinoid(s) (based on total cannabinoid weight) preferably 1%-70%.

In an embodiment of the invention, the daily dosage of the protein-boundcannabinoid, is between 0.1 microgram (μg) and 1500 milligram (mg). Someembodiments of the invention relate to treatments as monotherapy, inwhich a protein-bound cannabinoid is a sole active pharmaceutical agentused to treat a disease. Some embodiments of the invention relate tocombination therapies in which a protein-bound cannabinoid is used incombination with another active pharmaceutical agent to treat a disease.“In combination with” refers to both drugs being substantially effectivein the body at a same time. Both drugs can be administered substantiallyat the same time, or both drugs can be administered at different timesbut have effect on the body at the same time.

Method 100 may further comprise a block 60, which comprisesadministering the pharmaceutical composition to a patient in needthereof.

The above mentioned method 100 may be practiced with respect to opiumpoppy plant matter in order to obtain opioids, by replacing cannabisplant matter with opium poppy plant matter.

Reference is now made to FIG. 1B, which shows a flow-diagram depicting amethod 200 for the manufacture of compositions comprising cannabinoidsand/or for treatment of a patient in need thereof, in accordance withembodiments of the invention.

Method 200 comprises a block 110, which comprises producing cannabisextract from cannabis plant material. According to an embodiment of theinvention, cannabis plant material may be selected from one or more thanone of: leaves, flowers, trichomes, resin, tincture, extract and oil.According to an embodiment, cannabis plant material comprises acombination of leaves and flowers. According to an embodiment of theinvention, cannabis extract is prepared by contacting cannabis plantmaterial with a solvent. According to an embodiment the solventcomprises an alcohol. According to an embodiment of the invention, thealcohol comprises methanol or ethanol. According to an embodiment of theinvention, the solvent is a mixture of methanol and chloroform.

Method 200 may further comprise a block 120, which comprises contactingcannabis extract with an aqueous protein solution.

According to an embodiment of the invention, the protein is a plasmaprotein. According to an embodiment of the invention, the plasma proteinis one of or a combination of more than one of albumin, lipoprotein,glycoprotein, and α, β, and γ globulin or diluted blood plasma or eggalbumin (OVA). According to an embodiment of the invention, the plasmaprotein may be naturally occurring protein or recombinant protein.According to an embodiment of the invention, the albumin may comprisehuman serum albumin or bovine serum albumin or egg albumin or anycombination thereof.

Contacting the cannabis extract with an aqueous protein solution may beperformed using 0.1% to 33% cannabinoids extract (in solvent) in anaqueous solution. According to an embodiment of the invention, theaqueous solution is mixed slowly and/or incubated from a time between 10minutes and 48 hours.

According to an embodiment of the invention, the aqueous solutioncomprises at least one salt and at least one buffer. According to anembodiment of the invention, the solution is substantially isotonic withblood. According to an embodiment, the solution comprises Hartmann'ssolution. Alternatively, the solution may be water.

According to an embodiment of the invention the aqueous solutioncomprises between about 0.001% and about 80% plasma protein on aweight/volume (w/v) basis. According to an embodiment of the inventionthe aqueous solution comprises between about 0.01% and about 40% plasmaprotein on a w/v basis. According to an embodiment, the aqueous solutioncomprises about 20% (w/v) plasma protein.

Upon contacting a cannabis extract with an aqueous protein solution, theprotein in the aqueous solution may bind cannabinoids present in theextract, forming protein-bound cannabinoid. The otherwisewater-insoluble cannabinoid may then be dissolved in the aqueous proteinsolution.

Method 200 may further comprise a block 112, comprising smoke or vaporof cannabis plant matter. Smoke or vapor may be formed as in method 100,block 10.

Method 200 may further comprise a block 122, comprising contacting smokeor vapor with a solvent to form a cannabinoid solution. The solvent,according to an embodiment of the invention, may be an alcohol. Thealcohol may be ethanol.

Method 200 may further comprise a block 124, comprising contactingcannabinoid solution with an aqueous protein solution. Contacting ofblock 124 may be similar to the contacting of cannabis extract of block120, with the modification of substituting a cannabinoid solution for acannabis extract.

Method 200 may further comprise a block 130, which comprises analyzingthe aqueous protein solution. Analysis may be performed on a sample ofthe aqueous solution to determine the cannabinoid profile (identity andquantity) of the cannabis plant material. Analysis may be performedthrough chromatography, such as gas chromatography or HPLC.

Method 200 may further comprise a block 140, which comprises isolatingand/or purifying protein-bound cannabinoid. According to an embodimentof the invention, isolating and or purifying protein-bound cannabinoidmay comprise removing non-protein-bound dissolved compounds from thesolution. This may be performed by precipitating the protein-boundcannabinoid out of solution, for example, by adding a solvent or a saltto the solution or by denaturing the protein, for example, by heating.The precipitate may then be washed to remove non-protein bound dissolvedcomponents. According to an embodiment of the invention, purificationmay be performed through a pore-size gradient.

Alternatively or additionally, purification of protein-bound cannabinoidmay be performed by removal of water from the solution, according toembodiments of the invention. Removal of the water may be performed byvacuum, heating, lyophilization, or a combination of any of thesemethods.

Method 200 may further comprise a block 150, which comprises combining aprotein-bound cannabinoid with an excipient to form a pharmaceuticalcomposition.

The protein-bound cannabinoid according to an embodiment of theinvention may comprise one or more than one of the following: Δ9-THC,Δ8-THC, tetrahydrocannabinoic acid (THCA), CBD, cannabidiolic acid(CBDA), cannabinol (CBN), cannabigerol (CBG), tetrahydrocannabivarin(THCV), cannabigerolic acid CBGA and cannabichromene (CBC).

According to an embodiment of the invention, the cannabinoids present inthe protein-bound cannabinoid may be similar in profile as in thestarting cannabis extract produced in block 110.

Method 200 may further comprise a block 160, which comprisesadministering the pharmaceutical composition to a patient in needthereof.

The above mentioned method 200 may be practiced with respect to opiumpoppy plant matter in order to obtain opioids, by replacing cannabisplant matter with opium poppy plant matter. According to an embodimentof the invention, administration is performed through inhalation.Inhalation may comprise inhalation via the nasal route or via the mouth.According to an embodiment of the invention, administration is performedthrough sublingual or buccal administration, oral administration,transdermal administration or parenteral administration.

According to an embodiment of the invention, the pharmaceuticalcomposition is administered to the patient to treat a disease orcondition. According to an embodiment of the invention, the disease orcondition is selected from the group consisting of: conditions of painrelating to chemotherapy; conditions of pain and “wasting” syndrome inconnection with AIDS; nausea and vomiting, nausea and vomiting as sideeffects of a chemotherapy as well as in connection with AIDS orhepatitis; neuropathic pain; anorexia or cachexia; neurodegenerativedisease; hypoxia, comprising stroke or trauma; paralytic symptoms inconnection with multiple sclerosis or traumatic transverse lesions;dystonic motor disturbance; bronchial asthma; epileptic attacks orgeneralized epilepsy; withdrawal symptoms in connection with alcoholdependence, benzodiazepine dependence and opiate dependence; Parkinson'sdisease; dementia, Alzheimer's disease; arthritis; glaucoma; migraine;PTSD; Crohn's disease; tremor, Parkinsonian tremor; attention deficitdisorder; attention deficit hyperactivity disorder; irritable bowelsyndrome and dysmenorrhoea.

Example 1a: Formation of Protein-Bound Cannabinoid from Cannabis Smoke

Protein-bound cannabinoid was formed according to the following method.An aqueous albumin solution was prepared by adding 20 (mg)) of bovineserum albumin (BSA, from Millipore, USA) to 10 milliliters (ml) mlHartmann's solution (B. Braun Melsungen A G, Germany). BSA wascompletely dissolved using a shaker (Heidolph POLYMAX 1040) at 50revolutions per minute.

A cannabis-filled cigarette was formed using a cigarette papercontaining 0.8 gr ground cannabis (provided by “Seach” Israel), fromflowers and budding leaves. A Pasteur pipette was cut longitudinally atits wide end, and the cigarette was lodged in to the cut end. The narrowend of the pipette was attached to a syringe. The cigarette was lit in afume hood, and cigarette smoke was collected in the syringe by pullingthe syringe plunger. The smoke was then slowly released into the BSAsolution by depressing the plunger. Approximately 350 ml ofsmoke-containing air was gently bubbled through the BSA solution.

As a control, a solution of 10 ml of Hartmann's solution was preparedwithout the addition of BSA and a similar procedure of cannabis smokeformation and bubbling was performed.

Samples having a volume of 3 ml of the BSA solution and the controlsolution were each inserted in to HPLC glass vials and the open vialswere inserted into a vacuum oven for 24 hours at 37° Celsius.

The solid phase after the evaporation was crushed in to a fine powderusing mortar and pestle. The powder was extracted using Methanolchloroform 9:1 extract solution, sonicated for 30 minutes, and was thenfiltered and added in to an HPLC testing tube.

HPLC was performed using an HP1050 AGILENT, DAD detector, XBridge C183.5 μm 4.6×150 mm column, and according to the following parameters:

Mobile Phase A 50 mM ammonium formate in water at pH 3.75 with 10% ACNMobile Phase B Mobile phase B: 90% ACN/10% Water Diluentwater/acetonitrile (v/v: 5/5) Flow Rate 1 ml/min Injection 30 μl DrawSpeed 200 μl/min Eject Speed 200 μl/min Stop time 40 min Column 30° C.Temperature Detector Diode array detector Signal store 228 nanometers(nm, non-acidic cannabinoids) 270 nm (acidic cannabinoids), Storespectrum from 190-370 nm

Gradient Program:

Time (min) % A % B 0 30 70 15 10 90 30 10 90 31 30 70 40 30 70

Results:

HPLC showed that the BSA aqueous solution, after cannabis smoke wasintroduced to it, comprised many active cannabinoids including CBN,THCA, THC and CBC, which had dissolved in the solution. A correspondingchromatogram is shown in FIG. 2A, based on the 270 nm wavelength. Thechromatogram shows peak intensity (in units of milli-absorbance units,mAU) over time in minutes. On the other hand, in the control solutionwhich did not comprise proteins, no active cannabinoids were detected,as shown in FIG. 2B.

The inventors have shown that methods according to embodiments of theinvention may effectively dissolve significant amounts of activecannabinoids from cannabis smoke/vapor in aqueous solutions using plasmaproteins as agents to bind and enhance solubility of the cannabinoids.Aqueous solutions formed according to embodiments of the invention areadvantageous in that they can be easily quantified, purified andformulated into pharmaceutical compositions for administration in avariety of routes. The cannabanoids profile of the aqueous solution issimilar to that of the cannabis smoke/vapor, which has already beenshown to be effective in treatment of a variety of diseases whenadministered via the lungs. At the same time, plasma protein-boundcannabinoids can be administered with more accuracy and without thenegative lung health ramifications associated with smoking cannabis.

Example 1b: Formation of Protein-Bound Cannabinoids and Quantificationof Cannabinoids

In order to increase amount of protein-bound cannabinoid present inBSA/water solution according to example 1a, additional experimentationwas performed using varying amounts of additional solvents. The range ofbetween 25% and 33% ethanol was found to be particularly advantageous,particularly at 10 mg protein per ml of solution.

A solution was formed by forming a water solution having a concentrationof 10 mg/ml of BSA. 50 ml of the water solution was mixed with 25 ml ofethanol. A 1 g cigarette of cannabis (provided by Seach, Israel, BatchB12) was lit and smoke was bubbled through the BSA/water/ethanolsolution using the apparatus described in example 1a, but using a vacuumpump to gradually introduce the smoke into the solution via a gas trap.The solution foamed to a lesser extent than the solution used in example1a.

After introducing smoke into the solution, the solution was split intothree batches for incubation. Batch A was incubated for 1 hour at roomtemperature while stirring. Batch B was incubated at room temperaturefor 48 hours without stirring. Batch C was incubated at room temperaturefor 48 hours while stirring. Cannabinoid identity and quantity weredetermined by HPLC. The amount and type of cannabinoid varied based onthe incubation conditions, as follows:

Total Cannabinoid Content Batch per mg BSA A 0.45 micrograms (μg) B 1.96μg C 2.15 μg

It was found that aqueous protein solutions comprising 33% ethanol hadan approximately three-fold higher cannabinoid content per mg BSA thancorresponding aqueous protein solutions having no non-water solvent.

Example 1c: Formation of Protein-Bound Cannabinoids in SolutionsComprising Various Concentration of Protein/Solvent

30 micrograms of THC standard was dissolved in various amounts ofethanol (absolute) in various amounts, between 1.5 microliters and 15microliters. The THC solution was then combined with 0.5 ml of a 20microgram/ml solution of BSA. The resulting solutions each had a totalof 10 micrograms of BSA and 30 micrograms of THC, but varied in theirethanol content. As ethanol concentration increases, the adsorption ofTHC to protein increases. The results can be seen in FIG. 5 .

The inventors found that solutions having a concentration of over 33%ethanol, it was seen that protein precipitates and a cloudy mixture wasformed.

Example 1d: Formation of Protein-Bound Cannabinoids from Smoke and Vaporand Quantification Relative to Smoke or Vapor Absorbed in OrganicSolvents

To show which cannabinoid compounds are solubilized in processes usingBSA versus organic solvents, cannabis from two different batches wassmoked and or vaporized. Vapor was formed using a “volcano” vaporizer ata temperature of 210° C. The smoke/vapor was passed through either aBSA/water/ethanol solution described in example 1b, comprising 33% byvolume ethanol or through a pure ethanol (99% ethanol) solution.Solutions were stirred using a magnetic stirrer and were incubated for48 hours, during which time, most of the ethanol evaporated. One of thebatches of cannabis was high in THC, and the other batch of cannabis washigh in both THC and CBD.

The BSA/water/ethanol solution was washed after smoke or vapor wascombined with it, and the amount of cannabinoids present was analyzed.The results of the comparison of relative concentration of cannabinoids(relative to total cannabinoid content) as expressed in percent(weight/weight), for a strain of cannabis high in THC are shown in thetable below.

Smoke passed Vapor passed Smoke passed through through through BSA/Cannabinoid ethanol ethanol water/ethanol CBDA 0.9 0.4 0.0(Cannabidiolic Acid) CBGA 0.6 0.1 0.0 (Cannabigerolic acid) CBG 4.9 1.221.0 CBD 1.9 0.3 0.0 THCV 2.4 0.7 0.0 CBN 1.7 1.6 0.0 THCA 0.9 1.1 9.3THC 86.7 94.6 69.7 DELTA-8-THC 0.0 0.0 0.0 CBC 1.3 0.0 0.0

The results of the comparison of relative concentration of cannabinoids(relative to total cannabinoid content) as expressed in percent(weight/weight), for a strain of cannabis high in CBD and THC are shownin the table below.

Smoke Vapor passed passed Smoke passed Vapor passed through throughthrough BSA/ through BSA/ Cannabinoid ethanol ethanol water/ethanolwater/ethanol CBDA 2.3 1.6 39.8 23.6 CBGA 0.4 0.0 0.0 0.0 CBG 4.2 1.50.0 0.0 CBD 44.7 51.1 22.3 33.4 THCV 2.4 0.8 0.0 0.0 CBN 1.6 0.0 0.0 0.0THCA 0.7 0.3 5.3 0.0 THC 40.7 40.9 32.8 37.7 DELTA-8-THC 0.0 0.0 0.0 0.0CBC 3.1 3.8 0.0 5..3

As can be seen from the tables above, a different cannabinoid profile ispresent when smoke or vapor is contacted with BSA water solutionrelative to ethanolic solvent. It is suggested that the profile ofcannabinoid obtained when contacting with BSA water solution is similarto the profile absorbed in a human bloodstream after inhalation ofcannabis smoke or vapor.

Example 1e: Determination of Adsorption Capacity of BSA Using THCStandard

An albumin solution in water (20 μg/ml) and ethanol was prepared. THCstandard was added at concentrations of between 20 μg/ml and 60 μg/ml.The amount of THC adsorbed to the BSA protein was determined for eachconcentration after incubation for either two hours or 12 hours whilegently vortexing. The results are shown in FIG. 4 . As seen in thefigure, concentrations of above 50 μg adsorbed THC per mg of albumin canbe obtained. It is suggested that compositions according to embodimentsof the invention comprising mixtures of cannabinoids can be adsorbed toproteins in similar concentration ranges.

Example 1f: Formation of Protein-Bound Cannabinoid from Cannabis VaporUsing Additional Proteins

Vapor of cannabis plant material high in CBD was formed using a volcanovaporizer, and the vapor was streamed through 1 mg/ml solutions ofeither rice recombinant human serum albumin (HSA), bovine γ-globulin orovalbumin (hen). The protein solutions were formed using ethanol andwater in a 1:2 ratio. The solutions were incubated at 30° C. for 24hours. The percentage of each cannabinoid relative to total cannabinoidsadsorbed to protein was determined and is shown in the table below.

Rice recombinant Bovine Cannabinoid HSA γ-globulin Ovalbumin CBDA 46 02.4 CBGA 0 0 0 CBG 0 0 0 CBD 33 0 55.9 CBN 0 0 0 THCA 0 100 0 THC 21 041.7 CBC 0 0

These results indicated that HSA and ovalbumin act similarly to BSA. TheHSA and the ovalbumin each adsorbed about 4 micrograms of cannabinoidper mg of protein. On the other hand, γ-globulin adsorbed lower levelsof cannabanoid and a different profile.

Example 2a: Formation of Protein-Bound Cannabinoid from Cannabis Extract

Cannabis extract was prepared as follows: In short, cannabis plantmatter is dried, ground and homogenized to form ground cannabis. Theground cannabis is extracted with methanol/chloroform (volume/volumeratio of 9:1). Sonication and filtration is then performed. Identity ofcannabinoids is determined by HPLC by evaporation, dissolution in anappropriate solvent.

Drying of the cannabis plant matter occurs under high vacuum at about37±2° C. for about 24 hours and then ground to form a fine powder. 200mg of ground powder is combined with 10 ml of methanol/chloroform, andsonicated in an ice bath for 30 minutes at maximum power. Thesupernatant is then filtered through a 0.2 micron filter.

A sample of the cannabis extract was analyzed for content ofcannabinoids. The cannabis extract was then combined with albuminsolution having 20% ethanol at 10 mg/ml (BSA) and incubated for 2 hoursat room temperature. The percentage of each cannabinoid relative tototal cannabinoids adsorbed to protein was determined and is shown inthe table below.

Adsorbed to BSA after extract combined Cannabinoid Extract with BSAsolution CBDA 1 0 CBGA 3 2 CBG 3 1 CBD 0 0 CBN 2 2 THCA 22 29 THC 68 63CBC 1 3

This experiment shows a different profile than the profile ofcannabinoids in experiment 1 in which cannabinoids from vapor wereadsorbed in protein solutions. The weight ratio of adsorbed cannabinoidsto protein in this experiment was about 1 to 5.

Example 2b: Formation of Protein-Bound Cannabinoid from CannabinoidSolution

Cannabis buds, (3 g) from a high THC strain, obtained from Seach Ltd,Israel was rolled into cigarettes and was burnt or vaporized and theresulting smoke and vapor was combined with 200 ml ethanol. The 200 mlsolutions were concentrated to a volume of about 3 ml. The amount ofcannabinoids dissolved in ethanol from smoke and vapor was determinedand is described (in micrograms/ml) in the table below:

Vapor Smoke CBDA 3.1218 0 CBGA 28.7668 23.088 CBG 183.6224 292.063 CBD17.2726 0 CBN 135.5254 276.856 THCA 72.8432 83.765 THC 3777.77966195.223 CBC 54.7468 90.873 delta-8-THC 0 0 Total 4273.6786 6961.868Cannabinoids

100 microliters of ethanolic cannabinoid solution from cannabis vaporand cannabis smoke were each mixed with 500 microliters of aqueousalbumin solution that had been prepared at a concentration of 5 mgalbumin (BSA)/ml. The aqueous albumin solution combined with theethanolic cannabinoid solution was incubated at 30° C. for 12 hours inopen tubes. After 12 hours, the tubes were mixed and centrifuged, andnon-adsorbed cannabinoids were separated from the solution. Concentratedprotein-bound cannbinoid was dried and quantified as described below.

Vapor Smoke CBDA 0 0 CBGA 1.43 0.58 CBG 11.685 5.9 CBD 0 0 CBN 4.855 6.5THCA 4.26 2.16 THC 131.955 121.38 CBC 1.845 2.13 delta-8-THC 4.6 0 Total160.63 138.645 Cannabinoids

Example 3: Formation of Protein-Bound Opioid from Opium

Protein bound-opium may be formed using similar methods described withreference to protein-bound cannabinoids.

Example 4a: Biological Effect of Protein-Bound Cannabinoid Relative toNon-Bound Cannabinoid

The NFκB transcription factor plays a key role in inflammation, theimmune response, cell proliferation and protection against apoptosis.

The murine macrophage cell line RAW264.7 (obtained from the AmericanType Culture Collection) was transduced with an NF-κB luciferasereporter construct and used in the assay to determine inhibitory effectsof test compositions on NF-κB protein in cells containing the NF-κBluciferase reporter gene construct. The test compositions used were rawplant extract from cannabis high in THC and protein-bound cannabinoidmixture prepared from cannabis plant extract derived from the samecannabis plant material, prepared as described above. Inhibition wasdetermined at two doses, 1.56 micrograms per milliliter (μg/ml) and 0.78μg/ml of THCA. Plant extract was dissolved in medium before adding tocell culture. Lipopolysaccharide (LPS) was used to induce NF-κBluciferase reporter and the extracts were tested for inhibitoryactivity. Calcein AM (acetomethoxy derivate of calcein) was used as afluorescent dye to determine RAW264.7 cell number for normalization. Asluminescence in the model is correlated to activation of NF-κB,inhibition of expression can be determined by correlation withinhibition of luminescence.

Compositions with high percentage of inhibition in the model indicatetheir potential use to reduce inflammation by inhibition of NF-κBactivity in mammals. The effects of both plant extract and protein-boundcannabinoid on NF-κB luciferase reporter at concentrations of 1.56 and0.78 μg/ml of THCA were tested and are shown in FIG. 3 a . At bothconcentrations, protein-bound cannabinoid was more effective ininhibition NF-κB luciferase reporter induction than raw cannabis plantextract, indicating that protein-bound cannabinoid has enhancedanti-inflammatory properties relative to raw cannabis plant extract andis effective at lower doses.

In subsequent experiments, protein-bound cannabinoid was extensivelywashed using Amicon Ultra Centrifugal Filters having a cutoff of 30kilodaltons. Samples were washed with 0.5 ml of water and repeated 1, 2or 4 times. Samples washed 1, 2 and even 4 times showed similar effecton inhibition in the model, indicating that the cannabinoids werestrongly adsorbed by the albumin, however they maintained theirbioactive properties when exposed to cells.

Example 4b: Biological Effect of Protein-Bound Cannabinoid Relative toNon-Bound Cannabinoid

The in-vitro model described in example 4a was performed, comparingprotein-bound cannabinoid prepared from smoke and protein-boundcannabinoid prepared from vapor at a concentration of 6 micrograms/ml,prepared as described in example 2b. Protein alone, in an equivalentamount, was used as a control.

The effects of protein alone and protein-bound cannabinoid are shown inFIG. 3 b . Both protein-bound cannabinoid obtained from smoke andobtained from vapor were more effective in inhibition NF-κB luciferasereporter induction than protein alone.

Example 5a: In Vivo Testing of Cannabinoids According to Embodiments ofthe Invention in a Model of Appetite Increase

Mice (C57BL strain) are isolated from each other and fed at regularintervals for one week. Mice are grouped into groups of 4. After theweek of regular feeding, food is removed from each mouse's cage for 24hours. Thirty minutes before providing food, each mouse is administereda test drug, positive control (ethanolic cannabis extract or pure THC)or a negative control comprising vehicle only. A measured amount of foodis provided after the 24 hours without food. One hour and two hoursafter provision of the food, the remaining amount of food is weighed andcompared to the starting amount of food. Test mice are administered withone of the doses (1, 2, 3 or 6 mg of THC equivalent/kg of mouse weight)of protein-bound cannabinoid, in a phosphate buffered saline (PBS) in anamount of 100 microliters through either the intraperitoneal (IP), nasalor oral (gavage) routes. Positive control mice are administered 1, 2, 3or 6 mg of THC (or equivalent) in the form of ethanolic extract ofcannabis dissolved in PBS, or pure THC dissolved in ethanol, dissolvedin PBS in 100 microliters through either the intraperitoneal (IP), nasalor oral (gavage) routes. Negative control mice are administered ethanolin PBS through either the intraperitoneal (IP), nasal or oral (gavage)routes. Trials are repeated in triplicate and the results are tallied byblinded researchers.

It may be shown that mice administered doses of protein-boundcannabinoid are effective in increasing appetite in mice relative tomice receiving no active treatment. It is suggested that miceadministered doses of protein-bound cannabinoid may experience appetiteincrease to a greater extent than the mice administered equivalent dosesof non-protein bound cannabinoid.

Example 5b: In Vivo Testing of Cannabinoids According to Embodiments ofthe Invention in a Model of Neuropathy and Neuropathic Pain

Mice (C57BL strain) are grouped into groups of 8. Each mouse isadministered Vincristine throught the IP route, twice a week for 10weeks, at an amount of 1.7 mg/kg. Mice are administered test drug,positive control or negative control. The mice are tested once a weekfor sensitivity to pain using a hot plate, rotarod test and a tail flicktest, for 10 weeks. Test mice are administered with one of the doses (1,2, 3 or 6 mg of THC equivalent/kg of mouse weight) of protein-boundcannabinoid, in a phosphate buffered saline (PBS) in an amount of 100microliters through the nasal route. Positive control mice areadministered 1, 2, 3 or 6 mg of THC (or equivalent) in the form ofethanolic extract of cannabis dissolved in PBS, or pure THC dissolved inethanol, dissolved in PBS in 100 microliters through the nasal route.Negative control mice are administered ethanol in PBS through the nasalroute. Trials are repeated in triplicate and the results are tallied byblinded researchers.

It may be shown that mice administered protein-bound cannabinoidwithstand pain for longer, and thereby show longer time until tailflickor leglift upon hotplate testing, and show more success in rotarodtesting.

Example 5c: In Vivo Testing of Cannabinoids According to Embodiments ofthe Invention in a Model of Parkinson's Disease

Mice (C57BL strain) are grouped into groups of 8. Each mouse isadministered two doses, of 20 mg/kg of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with an hour waitbetween the administrations. After 48 hours, each mice is administeredanother two doses an hour apart from each other.

Mice are administered test drug and control as described in example 5b.Mice are tested for Parkinsonian symptoms using footprint analysis, arotarod test, a hot plate and a tailflick test.

It may be shown that mice administered protein-bound cannabinoid show animprovement in Parkinsonian symptoms induced by MPTP relative to micefrom control groups.

There is further provided in accordance with an embodiment of theinvention, a composition comprising at least one pharmaceuticallyacceptable excipient and at least one protein-bound cannabinoid bound toa plasma protein. Optionally, the composition further comprises water.Optionally, the composition is substantially free of water. Optionally,the plasma protein comprises one of or a combination of more than one ofalbumin, lipoprotein, glycoprotein, α, β, and γ globulin and dilutedblood plasma. Optionally, the protein comprises albumin. Optionally, thealbumin comprises human serum albumin, bovine serum albumin or eggalbumin (OVA). Optionally, plasma protein is a recombinant protein.Optionally, the composition comprises less than 10% non-protein-boundcannabinoid. Optionally, the ratio of protein to cannabinoid is between100:1 to 1:1 according to a weight/weight basis Optionally, the ratio ofprotein to cannabinoid is between 20:1 to 1:1 according to aweight/weight basis. Optionally, the cannabinoid is selected from thegroup consisting of: Δ9-THC, Δ8-THC, tetrahydrocannabinoic acid (THCA),CBD, cannabidiolic acid (CBDA), cannabinol (CBN), cannabigerol (CBG),tetrahydrocannabivarin (THCV), cannabigerolic acid CBGA andcannabichromene (CBC). Optionally, the composition further comprises anadditional active pharmaceutical agent. Optionally, the compositioncomprises a targeting moiety linked to the plasma protein.

There is further provided in accordance with an embodiment of theinvention, a method for the manufacture of a protein-bound cannabinoid,the method comprising: obtaining a cannabinoid or cannabis in a formselected from the group consisting of cannabis smoke, cannabis vapor,cannabinoid solution and cannabis extract; and combining the cannabinoidor cannabis with an aqueous solution or suspension comprising a plasmaprotein to form a protein-bound cannabinoid. Optionally, the methodcomprises, obtaining cannabis in a form selected from the groupconsisting of cannabis smoke, cannabis vapor and cannabis extract, andcombining the cannabis smoke, vapor or extract with an aqueous solutionor suspension comprising a plasma protein to form a protein-boundcannabinoid. Optionally, the method comprises, heating cannabis plantmatter to form the cannabis smoke or the cannabis vapor, and contactingthe smoke or vapor with the aqueous solution or suspension comprising aplasma protein. Optionally, the method comprises, heating cannabis plantmatter to form cannabis smoke or cannabis vapor, contacting the smoke orvapor with a solvent to form the cannabinoid solution; and combining thecannabinoid solution with the aqueous protein solution or suspensioncomprising a plasma protein. Optionally, the solvent is an alcohol.Optionally, the alcohol is ethanol. Optionally, the method comprises,isolating the protein-bound cannabinoid from solution. Optionally, thecannabinoid is burnt to form the smoke. Optionally, the methodcomprises, forming the cannabis extract by combining cannabis plantmatter with a solvent. Optionally, the solvent comprises an alcohol.Optionally, the solvent comprises methanol and chloroform. Optionally,the method comprises, removing non-protein-bound cannabinoids.Optionally, the plasma protein comprises one of or a combination of morethan one of albumin, lipoprotein, glycoprotein, α, β, and γ globulin anddiluted blood plasma. Optionally, the protein comprises albumin.Optionally, the albumin comprises human serum albumin, bovine serumalbumin or egg albumin (OVA). Optionally, the method comprises, afterremoving non-protein-bound cannabinoids, the resulting compositioncomprises less than 10% by weight non-protein-bound cannabinoid.Optionally, the protein-bound cannabinoid comprises one or more than oneof the cannabinoids selected from the group consisting of: Δ9-THC,Δ8-THC, tetrahydrocannabinoic acid (THCA), CBD, cannabidiolic acid(CBDA), cannabinol (CBN), cannabigerol (CBG), tetrahydrocannabivarin(THCV), cannabigerolic acid CBGA and cannabichromene (CBC). Optionally,the aqueous solution or suspension further comprises an alcohol.Optionally, the alcohol is present in a range of between 1% to about 33%of the solution. Optionally, the ratio of plasma protein to cannabinoidupon combining is between 2:3 and 1:10. Optionally, the method comprisesstirring the aqueous solution or suspension. Optionally, the aqueoussolution or suspension is stirred for about 24 to about 48 hours.Optionally, the aqueous solution or suspension is at a temperature ofabout 30° C. Optionally, the aqueous solution or suspension is undervacuum.

There is further provided in accordance with an embodiment of theinvention, a method for treating a disease comprising administering to apatient in need thereof a composition comprising at least onepharmaceutically acceptable excipient and at least one protein-boundcannabinoid bound to a plasma protein. Optionally, the disease isselected from the group consisting of: conditions of pain relating tochemotherapy; conditions of pain and “wasting” syndrome in connectionwith AIDS; nausea and vomiting, nausea and vomiting as side effects of achemotherapy as well as in connection with AIDS or hepatitis;neuropathic pain; anorexia or cachexia; neurodegenerative disease;hypoxia, comprising stroke or trauma; paralytic symptoms in connectionwith multiple sclerosis or traumatic transverse lesions; dystonic motordisturbance; bronchial asthma; epileptic attacks or generalizedepilepsy; withdrawal symptoms in connection with alcohol dependence,benzodiazepine dependence and opiate dependence; Parkinson's disease;dementia, Alzheimer's disease; arthritis; glaucoma; migraine; PTSD;Crohn's disease; tremor, Parkinsonian tremor; attention deficitdisorder; attention deficit hyperactivity disorder; irritable bowelsyndrome and dysmenorrhoea.

There is further provided in accordance with an embodiment of theinvention, a unit dose pharmaceutical composition comprising acomposition comprising at least one pharmaceutically acceptableexcipient and at least one protein-bound cannabinoid bound to a plasmaprotein. Optionally, the unit dose pharmaceutical composition comprisesan amount between 1 mg and 1 g. Optionally, the unit dose pharmaceuticalcomposition is in the form of a tablet, capsule, lozenge, wafer, patch,ampoule, vial, metered-dose inhaler or pre-filled syringe.

In the description and claims of the present application, each of theverbs, “comprise,” “include” and “have,” and conjugates thereof, areused to indicate that the object or objects of the verb are notnecessarily a complete listing of components, elements or parts of thesubject or subjects of the verb.

Descriptions of embodiments of the invention in the present applicationare provided by way of example and are not intended to limit the scopeof the invention. The described embodiments comprise different features,not all of which are required in all embodiments of the invention. Someembodiments utilize only some of the features or possible combinationsof the features. Variations of embodiments of the invention that aredescribed, and embodiments of the invention comprising differentcombinations of features noted in the described embodiments, will occurto persons of the art. The scope of the invention is limited only by theclaims.

WORKS CITED

-   Casano, S et al. “Variations in Terpene Proviles of Different    Strains of Cannabis sativa L. Aca Hort. 925, ISHS 2011.-   De Backer, B., 2009. Innovative development and validation of an    HPLC/DAD method for the qualitative and quantitative determination    of major cannabinoids in cannabis plant material. J. Chromatogr.,    Volume B 877, pp. 4115-4124. ElSohly, M. A. ed. Forensic Science and    Medicine: Marijuana and the Cannabinoids. Chapter II, pages 17-49-   Greydanus, D., 2013. Marijuana: current concepts. Frontiers in    Public Health, Volume 1, pp. 1-17.-   Melamede, R., 2005. Cannabis and tobacco smoke are not equally    carcinogenic. Harm Reduction Journal, 2(21).-   Naftali, T., 2011. Treatment of Crohn's Disease with Cannabis: IMAJ,    Volume 13, pp. 455-8.-   Pletcher, M., 2012. Association Between Marijuana Exposure. Journal    of American Medical Association, 307(2), pp. 173-181.

The invention claimed is:
 1. A method of treating chronic pain in ahuman suffering from chronic pain consisting essentially ofadministering to the human in need thereof a cannabinoid bound to aprotein selected from the group consisting of: albumin, α globulin, βglobulin, and γ globulin to effectively treat the chronic pain in thehuman in need thereof.
 2. The method according to claim 1, wherein thecannabinoid bound to the protein is in a pharmaceutical composition inthe form of a tablet, capsule, lozenge, wafer, sachet, patch, ampoule,vial, metered-dose inhaler or pre-filled syringe.
 3. The methodaccording to claim 2, wherein the pharmaceutical composition is in theform of a tablet or capsule.
 4. The method according to claim 1, whereinthe cannabinoid is selected from the group consisting of: Δ9-THC,Δ8-THC, tetrahydrocannabinoic acid (THCA), CBD, cannabidiolic acid(CBDA), cannabinol (CBN), cannabigerol (CBG), tetrahydrocannabivarin(THCV), cannabigerolic acid (CBGA) and cannabichromene (CBC).
 5. Themethod according to claim 4, wherein the cannabinoid is Δ9-THC.
 6. Themethod according to claim 4, wherein the cannabinoid is CBD.
 7. Themethod according to claim 2, wherein the amount of cannabinoid in thepharmaceutical composition is between 1 mg and 1 g.
 8. The methodaccording to claim 1, wherein the ratio of protein to cannabinoid isbetween 100:1 and 1:1 according to a weight/weight basis.
 9. The methodaccording to claim 8, wherein the ratio of protein to cannabinoid isbetween 20:1 and 1:1 according to a weight/weight basis.
 10. The methodaccording to claim 1, wherein the protein is albumin.
 11. The methodaccording to claim 10, wherein the albumin is selected from the groupconsisting of recombinant human albumin, human serum albumin, bovineserum albumin and egg albumin (ovalbumin).
 12. The method according toclaim 2, wherein the amount of protein-bound cannabinoid is between 0.1%and 95% of the pharmaceutical composition.
 13. The method according toclaim 12, wherein the amount of protein-bound cannabinoid is between 1%and 70% of the pharmaceutical composition.
 14. The method according toclaim 2, wherein the pharmaceutical composition comprises less than 10%by weight non-protein-bound cannabinoid.